Adenoviral low density lipoprotein receptor attenuates progression of atherosclerosis and decreases tissue cholesterol levels in a murine model of familial hypercholesterolemia

Familial is an autosomal codominant disease characterized by high concentrations of pro-atherogenic lipoproteins and premature atherosclerosis secondary to low density lipoprotein receptor (LDLr) deficiency. In the current study, the effects of gene transfer With 5 x 10(10) particles of E1E3E4-deleted adenoviral vectors expressing the LDLr (AdLDLr) or VLDLr (AdVLDLr) under control of the hepatocyte-specific human alpha(1)-antitrypsin promoter and 4 copies of the human apo E enhancer in C57BL/6 LDr(-/-) mice were investigated. Evaluation was performed in both sexes and in mice fed either standard chow or an atherogenic diet containing 0.2% cholesterol and 10% coconut oil. Compared to control mice, AdLDLr and AdVLDLr persistently decreased plasma non-HDL cholesterol in both sexes and oil both diets. Six months after LDLr gene transfer in mice led the atherogenic diet, average intimal area was 2.5-fold (p<0.01) and 3.2-fold (p < 0.001 lower in male and female mice. respectively, compared to controls. In mice fed standard chow, intimal area was, reduced 22-fold (p < 0.001 and 21-fold (p < 0.001) after LDLr gene transfer in male and female mice. respectively. We show that non-HDL lipoproteins are more atherogenic in female mice. independent of sex differences of plasma HDL cholesterol levels. and that saturated fat does not have an effect on atherosclerosis Independent of plasma cholesterol levels. Finally, quantification of tissue cholesterol levels indicates that AdLDLr does not induce cholesterol accumulation in the liver and reduces cholesterol content in the myocardium, quadriceps muscle and kidney. In conclusion, hepatocyte-specific LDLr gene transfer significantly improves cholesterol homeostasis in LDLr-/- mice. (C) 2008 Elsevier Ireland Ltd. All rights reserved,